- Synthesis of Mannich base derivatives of berberine and evaluation of their anticancer and antioxidant effects
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The 9-demethylated derivative of the isoquinoline alkaloid berberine was derivatised in its isoquinoline moiety using enamines derived from formaldehyde and morpholine, piperidine, carbazole and six variously substituted piperazines to form Mannich base products which were evaluated for their in vitro biological effects. Standard tests determined their radical scavenging potential and their ferric reducing antioxidant power (FRAP). Cancerous growth inhibitory efficacies were assessed using cervical cancer cell lines HeLa and CaSki and their cytotoxicities towards normal cell lines were evaluated using Madin-Darby canine kidney (MDCK) cell lines. Piperazine derivatives bearing a heterocyclic nitrogen substituent such as a pyridyl or a pyrimidyl ring were the most active antioxidant and anticancer agents. A carbazole moiety attached to the berberine core also demonstrated excellent inhibitory effects on cancerous cells.
- Mistry, Bhupendra,Patel, Rahul V.,Keum, Young Soo,Noorzai, Rafi,Gansukh, Enkhtaivan,Kim, Doo Hwan
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- Deciphering the positional impact of chlorine in a new series of berberine analogues towards the superb-selective "turn-on" hydrophobic signaling of bovine serum albumin at physiological pH
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The optical signals of serum albumin (SA) provide precious information for realizing its native functions, in addition to developing related biomedical applications. Herein, we report a new class of easy synthesizable and water-soluble compounds (BZ1-BZ5) based on different chlorine positions on 9-O-benzyl-substituted berberine scaffolds for the selective detection of bovine serum albumin (BSA) in CP buffer solution (10 mM, pH 7.2) based on two competing factors: hydrophobic interactions and steric repulsion. The frail emission intensities of these probes were enhanced upon the addition of BSA; exceptionally, a remarkable increase in emission intensity (140-fold) and remarkable lifetime and quantum yield increases make BZ4 an excellent fluorescence turn-on hydrophobic BSA sensor. Selectivity and co-existence studies involving other proteins, free tryptophan, etc. revealed that the microenvironment around the tryptophan moiety in BSA incites drastic spectral changes upon the introduction of BSA. Moreover, the most efficient lumino-probe, BZ4, can detect bovine serum albumin at a nanomolar level (LOD = 3.3 nM) with a broadened range of linearity and slight altering of the secondary structure of the protein. Our experimental results and docking simulation studies show that the probe BZ4 binds preferentially at "binding site II" of BSA. In addition, the binding and conformational alterations of BSA provoked by these analogues have been intensely investigated, and we fruitfully relate the binding results to the sensing outcome. The obtained results reveal how the different positioning of chlorine in benzyl-substituted berberine affects the hydrophobic sensing of BSA, making these probes a new category of BSA selective material with potential applications in proteome research.
- Jana, Gopal Chandra,Nayim, Sk,Sahoo, Nandan Kumar,Das, Somnath,Aktara, Mt Nasima,Patra, Anirudha,Islam, Md. Maidul,Hossain, Maidul
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- Synthesis of berberine-piperazine conjugates as potential antioxidant and cytotoxic agents
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Piperazine derivatives bearing different electron-withdrawing and electron-donating functional groups were linked to the well-known isoquinoline alkaloid derivative, berberine via efficient organic transformations. The entire target berberine-based analogues were examined for their in vitro antioxidant potency using 2,2-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid bioassays, and anticancer activities using sulforhodamine B assay against HeLa and CaSki cervical cancer cell lines in addition to the cytotoxicity using Madin-Darby canine kidney non-cancer cell lines and, ascorbic acid and berberine used as a control for antioxidant and anticancer activities, respectively. Bioassay results revealed that newer compounds were more active against CaSki and HeLa cell lines with therapeutic indices better than that of parent berberine and showed tolerable cytotoxicity to the normal cells. A final analogue 5a with 4-methylpiperazine substituent indicated most significant anticancer potency with a therapeutic index of 58.53 (HeLa) and 48.76 (CaSki), followed by those bearing meta-chloropiperazine rings with a therapeutic index of 41.83 (HeLa) and 47.35 (CaSki), respectively.In addition, newly synthesized analogues exerted a significant radical scavenging activity against 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid cation with IC50 values of 8.917 μg/mL, and were good to moderate scavengers of 2,2-diphenyl-1-picrylhydrazyl radical with IC50 values of 25.40 μg/mL. Synthesized compound was characterized using several techniques, fourier transform infrared spectroscopy, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, mass spectroscopy and elemental (CHN) analyses.
- Mistry, Bhupendra,Keum, Young Soo,Pandurangan, Muthuraman,Patel, Rahul V.,Kim, Doo Hwan
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- Antibacterial activity and structure-activity relationships of berberine analogs
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Analogs of berberine 1 and related compounds were prepared to evaluate structure-activity relationships. Among the 13-alkyl-substituted and the 13- unsubstituted protoberberinium salts, the 13-ethyl-9-ethoxyl homolog 30, the 13-ethyl analog 29, and the 13-methyl derivative 3 showed an increase in antibacterial activity against Staphylococcus aureus by eight-, four- and twofold respectively over the parent base berberine 1; this is suggestive that steric effects play a significant role in the antibacterial activity. Reduction of the protoberberinium salts yielding the tetrahydro derivatives greatly reduced the antibacterial activity. Replacement of methoxyl groups at the C-2 and the C-3 of ring A by a methylcnedioxy group resulted in increased antibacterial activity. These data strongly suggest that the quaternary nitrogen atom such as in protoberberinium salts, an alkylsubstituent at C- 13, and a methylenedioxy function at C-2 and C-3 are required for enhanced activity. Tetrahydroprotoberberine α-N-metho salts showed higher activity than tetrahydroprotoberberine hydrochlorides, but appreciably lower activity than protoberberinium salts. The effects of substitution at C-13 and on ring A in the α-N-metho salt were similar to those in protoberberinium salts. Stereochemical changes of the B/C ring juncture from trans to cis, and of the methyl group at C-13 from α to β, had, respectively, marked and slight effects on the activity. The tested compounds were less active against Escherichia coli (Gram-negative bacterium) and Candida albicans (fungus) than S aureus (Gram-positive bacterium).
- Iwasa,Kamigauchi,Ueki,Taniguchi
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- Berberine and its metabolites: Relationship between physicochemical properties and plasma levels after administration to human subjects
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Berberine (1) is an alkaloid used widely in the treatment of several diseases. However, its physicochemical properties, pharmacokinetics, and metabolism remain unclear, and conflicting data have been reported. In this study, the main physicochemical properties of 1 and its metabolites were evaluated, including lipophilicity, solubility, pKa, and albumin binding. A sensitive HPLC-ESIMS/MS method was developed and validated to identify 1 and its main metabolites in human plasma. This method was used to quantify their levels in the plasma of healthy volunteers and hypercholesterolemic patients following a single dose and chronic administration, respectively. In both cases, berberrubine (2) was found to be the main metabolite. Surprisingly, 2 is more lipophilic than 1, which suggests that this compound tautomerizes to a highly conjugated, electroneutral quinoid structure. This was confirmed by NMR studies. These results indicate that the higher plasma concentration of 2 was a consequence of a more efficient intestinal absorption, suggesting that berberrubine is potentially more pharmacologically active than berberine.
- Spinozzi, Silvia,Colliva, Carolina,Camborata, Cecilia,Roberti, Marinella,Ianni, Cristina,Neri, Flavia,Calvarese, Claudio,Lisotti, Andrea,Mazzella, Giuseppe,Roda, Aldo
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- Discovery of novel berberine derivatives with balanced cholinesterase and prolyl oligopeptidase inhibition profile
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Berberine, a naturally occurring compound, possesses an interesting multipotent pharmacological profile potentially applicable for Alzheimer's disease (AD) treatment. In this study, a series of novel 22 berberine derivatives was developed and tested in vitro. Berberine core was substituted at position 9-O of its aromatic ring region. All the hybrids under the study revealed multi-targeted profile inhibiting prolyl oligopeptidase, acetylcholinesterase and butyrylcholinesterase highlighting 4a, 4g, 4j, 4l and 4s possessing balanced activities in the micromolar range. The top-ranked candidates in terms of the most pronounced potency against POP, AChE and BChE can be classified as 4d, 4u and 4v, bearing 4-methylbenzyl, (naphthalen-2-yl)methylene and 1-phenoxyethyl moieties, respectively. In vitro data were corroborated by detailed kinetic analysis of the selected lead molecules. 4d, 4u and 4v were also inspected for their potential to inhibit aggregation of two abberant proteins in AD, namely amyloid beta and tau, indicating their potential disease-modifying properties. To explain the results of our study, we carried out docking simulation to the active sites of the respective enzyme with the best berberine derivatives, along with QSAR study. We also investigated compounds’ potential permeability through blood-brain barrier by applying parallel artificial membrane permeation assay and addressed their cytotoxicity profile.
- Sobolova, Katerina,Hrabinova, Martina,Hepnarova, Vendula,Kucera, Tomas,Kobrlova, Tereza,Benkova, Marketa,Janockova, Jana,Dolezal, Rafael,Prchal, Lukas,Benek, Ondrej,Mezeiova, Eva,Jun, Daniel,Soukup, Ondrej,Korabecny, Jan
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- Discovery of 2-aminothiazolyl berberine derivatives as effectively antibacterial agents toward clinically drug-resistant Gram-negative Acinetobacter baumanii
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Aminothiazolyl berberine derivatives as potentially antimicrobial agents were designed and synthesized in an effort to overcome drug resistance. The antimicrobial assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungi including drug-resistant pathogens, and the aminothiazole and Schiff base moieties were helpful structural fragments for aqueous solubility and antibacterial activity. Especially, aminothiazolyl 9-hexyl berberine 9c and 2,4-dichlorobenzyl derivative 18a exhibited good activities (MIC = 2 nmol/mL) against clinically drug-resistant Gram-negative Acinetobacter baumanii with low cytotoxicity to hepatocyte LO2 cells, rapidly bactericidal effects and quite slow development of bacterial resistance toward A. baumanii. Molecular modeling indicated that compounds 9c and 18a could bind with GLY-102, ARG-136 and/or ALA-100 residues of DNA gyrase through hydrogen bonds. It was found that compounds 9c and 18a were able to disturb the drug-resistant A. baumanii membrane effectively, and molecule 9c could not only intercalate but also cleave bacterial DNA isolated from resistant A. baumanii, which might be the preliminary antibacterial action mechanism of inhibiting the growth of A. baumanii strain. In particular, the combination use of compound 9c with norfloxacin could enhance the antibacterial activity, broaden antibacterial spectrum and overcome the drug resistance.
- Gao, Wei-Wei,Gopala, Lavanya,Bheemanaboina, Rammohan R. Yadav,Zhang, Guo-Biao,Li, Shuo,Zhou, Cheng-He
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- Synthesis, hypolipidemic and antifungal activity of tetrahydroberberrubine sulfonates
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The paper describes the synthesis of new tetrahydroberberrubine derivatives containing polyfl uorophenyl- or alkylsulfonate groups at the O(9) position as well as those containing or not containing a bromine atom at the C(12) position. In a model of acute Triton-induced hyperlipidemia, tetrahydroberberrubine 9-O-(heptafluoro-4’-toluene)sulfonate was shown to reduce the cholesterol level by 23.5%, which is comparable with the eff ect of Simvastatin. At a concentration of 32 μg mL?1, tetrahydroberberrubine 9-O-pentafluorobenzenesulfonate inhibits the growth of the fungus Cryptococcus neoformans by 81.3±3.5%.
- Nechepurenko,Shirokova,Khvostov,Frolova,Sinitsyna,Maksimov,Bredikhin,Komarova,Fadeev,Luzina,Tolstikova,Salakhutdinova
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- Discovery of natural berberine-derived nitroimidazoles as potentially multi-targeting agents against drug-resistant Escherichia coli
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A series of natural berberine-derived nitroimidazoles as novel antibacterial agents were designed, synthesized and characterized by nuclear magnetic resonance (NMR), infrared spectra (IR), and high resolution mass spectra (HRMS) spectra. The antimicrobial evaluation showed that some target molecules exhibited moderate to good inhibitory activities against the tested bacteria and fungi including clinical drug-resistant strains isolated from infected patients. Especially, 2-fluorobenzyl derivative 8f not only gave strong activity against drug-resistant E. coli with the minimal inhibitory concentration (MIC) value of 0.003 mM, 33-fold more active than norfloxacin, but also exhibited low toxicity toward RAW 264.7 cells and less propensity to trigger resistance. The aqueous solubility and ClogP values of target compounds were investigated to elucidate the structureactivity relationships. Molecular docking and quantum chemical studies for compound 8f rationally explained its antibacterial effect. The further exploration of antibacterial mechanism revealed that the highly active compound 8f could effectively permeabilize E. coli cell membrane and intercalate into DNA isolated from resistant E. coli to form 8f-DNA complex that might block DNA replication to exert the powerful bioactivities. Compound 8f could also selectively address resistant E. coli from a mixture of various strains.
- Zhang, Guo-Biao,Maddili, Swetha Kameswari,Tangadanchu, Vijai Kumar Reddy,Gopala, Lavanya,Gao, Wei-Wei,Cai, Gui-Xin,Zhou, Cheng-He
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- Two telomerase-targeting Pt(ii) complexes of jatrorrhizine and berberine derivatives induce apoptosis in human bladder tumor cells
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Two novel Pt(ii) complexes, [Pt(B-TFA)Cl]Cl (Pt1) and [Pt(J-TFA)Cl]Cl (Pt2) with jatrorrhizine and berberine derivatives (B-TFA and J-TFA) were first prepared as desirable luminescent agents for cellular applications and potent telomerase inhibitors, which can induce bladder T-24 tumor cell apoptosis by targeting telomerase, together with induction of mitochondrial dysfunction, telomere DNA damage and cell-cycle arrest. Importantly, T-24 tumor inhibition rate (TIR) was 50.4% for Pt2, which was higher than that of Pt1 (26.4%) and cisplatin (37.1%). Taken together, all the results indicated that jatrorrhizine and berberine derivatives Pt1 and Pt2 show low toxicity and could be novel Pt-based anti-cancer drug candidates.
- Qin, Qi-Pin,Wang, Zhen-Feng,Huang, Xiao-Ling,Tan, Ming-Xiong,Luo, Zhi-Hui,Wang, Shu-Long,Zou, Bi-Qun,Liang, Hong
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- Synthesis, antioxidant and anticancer screenings of berberine-indole conjugates
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A variety of heterocyclic nitrogen cores in the form of indole moieties were linked to the natural isoquinoline alkaloid molecule berberine to achieve anticipated antioxidant and anticancer properties. An efficient synthetic pathway afforded final compounds 5a-j, which were tested in vitro for antioxidant potency using 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radical (ABTS) bioassays, and for anticancer activity using sulforhodamine B (SRB) assay against HeLa and Caski cancer cell lines. Moreover, the toxic nature of the resultant molecules was investigated using Madin-Darby canine kidney cells. The therapeutic indices of 5a-j were more appreciable against the Caski than HeLa cell line, in which compounds with electron-releasing alkyl or alkoxy functional group on indole entity as well as azaindole derivative performed well. In addition, these compounds were well endowed with antioxidant properties, in addition to the equal antioxidant effect of the compound with electron-withdrawing chlorine atom within indole entity. Adequate confirmation of the structure of the final analogues was achieved using Fourier-transform infrared (FT-IR), 1H nuclear magnetic resonance (NMR), and mass spectroscopy and elemental (CHN) analysis.
- Mistry, Bhupendra,Keum, Young-Soo,Kim, Doo Hwan
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- Design, synthesis and biological evaluation of novel Schiff base-bridged tetrahydroprotoberberine triazoles as a new type of potential antimicrobial agents
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A series of novel Schiff base-bridged tetrahydroprotoberberine (THPB) triazoles were designed, synthesized and characterized for the first time. Antimicrobial assay showed that some of the prepared compounds exerted stronger antibacterial and antifungal activities than the reference drugs. Especially, THPB triazole 7a gave low MIC values of 0.5, 1 and 2 μg mL-1 against B. yeast, M. luteus and MRSA, respectively. Further experiments indicated that the highly active molecule 7a was able to rapidly kill the MRSA strain and did not trigger the development of bacterial resistance even after 14 passages. The preliminary exploration for the antimicrobial mechanism revealed that compound 7a could effectively intercalate into calf thymus DNA to form a 7a-DNA supramolecular complex, and its Zn2+ complex had the ability to directly cleave pUC19 DNA, which suggested that compound 7a might be a potentially dual-targeting antibacterial molecule. It was also found that compound 7a could be efficiently stored and carried by human serum albumin (HSA), and the hydrophobic interactions and hydrogen bonds played important roles in the transportation of HSA to the active molecule 7a.
- Duan, Jun-Rong,Liu, Han-Bo,Jeyakkumar, Ponmani,Gopala, Lavanya,Li, Shuo,Geng, Rong-Xia,Zhou, Cheng-He
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- Synthesis and anticancer activity of a novel series of 9-O-substituted berberine derivatives: A lipophilic substitute role
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To alter its hydrophobicity, a series of compounds bearing 9-O-alkyl- or 9-O-terpenyl- substituted berberine were synthesized and evaluated for anticancer activity against human cancer HepG2 and HT29 cell lines. We found that the lipophilic substitute of 9-O-alkyl- and 9-O-terpenyl berberine derivatives plays a role in inhibiting the human cancer cell growth and its activity could be maximized with the optimized substitute type and chain length. Most strikingly, nonetheless, of the six compounds prepared, sample 8, a farnesyl 9-O-substituted berberine, showed either comparable or better cytotoxic activity against human cancer HepG2 cell line than that of berberine. Compound 8 had also shown a 104-fold antiproliferation activity in compare with berberine against human hepatoma HepG2 cell lines after 48 incubation hours. Further, in Hoechst 33258 and annexin V-FITC/PI staining analyses it induced apoptosis in HepG2 cells at lower concentration than that of berberine for 24 h. Take all; farnesyl 9-O-substituted berberine could be a potential candidate for new anticancer drug development.
- Lo, Chih-Yu,Hsu, Lin-Chen,Chen, Min-Shin,Lin, Yi-Jing,Chen, Lih-Geeng,Kuo, Cheng-Deng,Wu, Jin-Yi
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- Synthesis and anticancer activity of novel 9-O-substituted berberine derivatives
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Berberine is a bioactive isoquinoline alkaloid derived from many plants. Although berberine has been shown to inhibit growth and induce apoptosis of several tumor cell lines, its poor absorption and moderate activity hamper its full therapeutic potential. Here, we describe the synthesis of a series of 9-O-substituted berberine derivatives with improved antiproliferative and apoptosis-inducing activities. An analysis of novel berberine derivatives by EPR spectroscopy confirmed their similar photosensitivity and analogous behavior upon UVA irradiation as berberine, supporting their potential to generate ROS. Improved antitumor activity of novel berberine derivatives was revealed by MTT assay, by flow cytometry and by detection of apoptotic DNA fragmentation and caspase-3 activation, respectively. We showed that novel berberine derivatives are potent inhibitors of growth of HeLa and HL-60 tumor cell lines with IC50 values ranging from 0.7 to 16.7 μM for HL-60 cells and 36 to >200 μM for HeLa cells after 48 h treatment. Further cell cycle analysis showed that the observed inhibition of growth of HL-60 cells treated with berberine derivatives was due to arresting these cells in the G2/M and S phases. Most strikingly, we found that berberine derivative 3 (9-(3-bromopropoxy)-10-methoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a] isoquinolin-7-ylium bromide) possesses 30-fold superior antiproliferative activity with an IC50 value of 0.7 μM and 6-fold higher apoptosis-inducing activity in HL-60 leukemia cells compared to berberine. Therefore, further studies are merited of the antitumor activity in leukemia cells of this berberine derivative.
- Milata, Viktor,Svedova, Alexandra,Barbierikova, Zuzana,Holubkova, Eva,Cipakova, Ingrid,Cholujova, Dana,Jakubikova, Jana,Panik, Miroslav,Jantova, Sona,Brezova, Vlasta,Cipak, Lubos
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- Synthesis, characterization, and biological evaluations of 1,3,5-triazine derivatives of metformin cyclization with berberine and magnolol in the presence of sodium methylate
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The novel target products were synthesized in the formation of a triazine ring from berberine, magnolol, and metformin catalyzed by sodium methylate. The structures of products 1-3 were firstly confirmed by extensive spectroscopic analyses and single-crystal X-ray diffraction. The crystal structures of the target product 2 and the intermediate product 7b were reported for the first time. All target products were evaluated for their anti-inflammatory and antidiabetic activities against INS-1 and RAW264.1 cells in vitro and all products showed excellent anti-inflammatory effects and anti-insulin resistance effects. Our studies indicated that new compounds 1-3 were found to be active against inflammation and insulin resistance.
- Cao, Han,Liao, Shili,Zhong, Wenjing,Xiao, Xuerong,Zhu, Jiancheng,Li, Weimin,Wu, Xia,Feng, Yifan
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- A novel berberine-based colorimetric and fluorometric probe for Hg2+ detection and its applications in water samples
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The development of small molecule fluorescent probes for detection of heavy metal ions is highly desirable in fluorescent sensors area, and mercury (Hg2+) is a heavy metal pollutant in environment and food chain processes. Herein, we reported the design and synthesis of a novel berberine-based fluorescent probe P1, which can specifically recognize Hg2+ in CH3OH/PBS (8:2, v/v, pH = 7.4, 10 mM) solution by the colorimetric and fluorometric changes. The probe P1 displayed high selectivity, superior sensitivity and fast response toward Hg2+ with a low detection limit and a wide range of pH values. This probe can provide a convenient and effective way for Hg2+ detection on test paper strips. Moreover, the probe P1 can be applied to quantitatively detect Hg2+ in real environmental water samples.
- Gao, Yu,Li, Mingxin,Ruan, Shutang,Wang, Shifa,Wang, Zhonglong,Wu, Suzhen,Yang, Lijuan,Yang, Yiqin,Zhang, Yan
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- Synthetic and antitumor comparison of 9-O-alkylated and carbohydrate-modified berberine derivatives
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Abstract: Berberine is a naturally occurring isoquinoline alkaloid with moderate antitumor effect. It has been proved that berberine can affect the microenvironment of cancer cells, which is critical for cancer therapy and improving human immunity. Therefore, structural modification of berberine to obtain derivatives with high antitumor effect attracts the great attention of scientists. This paper describes the synthesis and in vitro antitumor investigation of some 9-O-alkylated and carbohydrate-modified berberine derivatives using high efficient strategy. The cytotoxicity investigation was accomplished on different cancer cell lines by the well-optimized MTT assay, and the results indicated that 9-O-hydrophobic modified berberine derivative 9 with long lipid chain showed promising in vitro antitumor activity with the IC50 value as low as 4.87 ± 0.24?μM. Percentage of apoptosis was measured by a Hoechst 33342/PI staining strategy on HeLa cells, which revealed that compound 9 could induce 84% of cell apoptosis at very low concentration (5?μM). Flow cytometry analysis indicated that compound 9 might inhibit HeLa cell proliferation by G2 phase arrest. The expression of various cell apoptosis proteins was measured by western blot analysis, and the results indicated that compound 9 could induce over-expression of Caspase-3, Parp, and Bax and down-regulate the expression of P53 and PCNA. All these data indicated the high potential of compound 9 for developing novel anticancer drugs. Graphic Abstract: [Figure not available: see fulltext.]
- Wang, Rongchun,Rostyslav, Stoyka,Li, Xiaobin,Lin, Houwen,Zhang, Xuanming,Zhang, Shanshan,Liu, Kechun,Wang, Lizhen
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- Experimental and quantum-chemical study of nucleophilic substitution mechanism in berberine
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Principal differences in the interaction mechanisms of alkaloid berberine with primary and secondary amines were investigated experimentally and by quantum-chemical calculations according to density functional theory (DFT/B3LYP) with 6-31G** basis set. The nucleophilic substitution of 9-metoxy group with primary amine was shown to proceed through a stage of σ-complex formation and led to 9-alkylamino derivatives of berberine. Analogous substitution with a secondary amine did not occur due to unfavorable thermodynamic parameters. The secondary amine participated in this reaction not as the attacking nucleophile, but rather as a bifunctional catalyst of berberine hydrolysis to berberrubine. The driving force for all these processes was the stabilization of products by hydrogen bonding. Based on the obtained results, we developed a new effective method for the preparation of berberrubine, one of the key intermediates in synthetic transformations of berberine. New 9-monoalkylamino derivatives of berberine containing indole moieties were synthesized.
- Burov, Oleg N.,Kletskii, Mikhail E.,Fedik, Nikita S.,Kurbatov, Sergey V.,Lisovin, Anton V.
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- Design, synthesis and biological evaluation of a hybrid compound of berberine and magnolol for improvement of glucose and lipid metabolism
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The discovery and structural optimization of lead compounds is the main task in the research and development of new drugs. In order to search for new compounds with greater activities and lower toxicity, the synthesis of two or more basic structures of drugs bonded together has been designed on the basis of combination principles. Here, a hybrid compound consisting of berberine (Ber) and magnolol (Mag) was synthesized and its biological activities were evaluated. We named the hybrid compound Huanghousu (HHS), and its size and structure were confirmed by spectroscopy (1H NMR, 13C NMR and HRMS spectra). The LD50 of HHS was determined in NIH mice by intraperitoneal injection according to the modified Karber's method. Treatment of transgenic aP2-SREBP-1c mice with HHS markedly reduced blood triglycerides (TG) and improved sugar tolerance. In addition, we also evaluated the effects of berberine, magnolol and HHS on the proliferation and differentiation of 3T3-L1 preadipocytes and investigated the underlying mechanism. The adipocyte differentiation-related genes PPARγ and C/EBPα were tested using a real-time quantitative polymerase chain reaction (real-time PCR). In addition, FAS, UCP2 and adiponectin mRNA, which are related to adipocyte adipogenesis, were also measured in mature 3T3-L1 adipocytes induced by differentiation medium. The efficacy of HHS in preventing obesity was somewhat greater than that of magnolol or berberine. Taken together, these results indicated that HHS was effective in improving disorders of glucose and lipid metabolism in vivo and regulating lipid metabolism-related gene expression in vitro.
- Li, Yan,Yuan, Xiao,Rong, Xianglu,Gao, Ying,Qiu, Zhibin,Zhang, Zhipeng,Zhou, Dongbin,Li, Weimin
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- Synthesis and evaluation of 9-O-substituted berberine derivatives containing aza-aromatic terminal group as highly selective telomeric G-quadruplex stabilizing ligands
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A series of new 9-O-substituted berberine derivatives (4a-j) as telomeric quadruplex ligands was synthesized and evaluated. The results from biophysical and biochemical assay indicated that introducing of positive charged aza-aromatic terminal group into the side chain of 9-position of berberine significantly improved the binding ability with G-quadruplex, and exhibited the inhibitory effect on the hybridization and on telomerase activity. These derivatives showed excellent selectivity for telomeric G-quadruplex DNA over duplex.
- Ma, Yan,Ou, Tian-Miao,Tan, Jia-Heng,Hou, Jin-Qiang,Huang, Shi-Liang,Gu, Lian-Quan,Huang, Zhi-Shu
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- Synthesis of piperazine based N-Mannich bases of berberine and their antioxidant and anticancer evaluations
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Isoquinoline alkaloids possess versatile biological activities. Hence, in the current research an effort has been made to improve structurally important part of isoquinoline alkaloid berberine because it is recognized as the marking compound for the crude drugs. Synthesis of rationalized berberine has been performed via substituting various piperazine moieties bearing disubstituted electron withdrawing and electron donating groups to the berberine core via Mannich reaction. Intended scaffolds were inspected for their in vitro antioxidant potential using different bioassays, FRAP, DPPH and ABTS as well as anticancer efficacies against cervical cancer cell lines HeLa, CaSki adapting SRB assay. Also, an inspection of the cytotoxic nature of titled analogues has been carried out towards Madin-Darby canine kidney (MDCK) cell lines. Radical scavenging potential of the final derivatives 4a-i was found to be excellent with IC50s, 3+ decreasing power with absorption at around 2 nm in FRAP assay. Moreover, compounds 4a-i appeared with significant inhibitors of the cervical cancer cell lines HeLa and CaSki with IC50s ranging 4.346-6.321 and 3.408-6.081 μg/mL, with low level of cytotoxic values and higher therapeutic indices ranging 20.42-42.45 and 21.23-43.25, respectively. Therefore, from the bioassay results it can be mentioned that these analogues are effective double agents as the scavengers of reactive oxygen species and inhibitors of the cancerous cells. The correct structure of the final compounds was adequately confirmed on the basis of FT-IR, 1H NMR and mass spectroscopy data as well as elemental analyses.
- Mistry, Bhupendra,Keum, Young-Soo,Noorzai, Rafi,Gansukh, Enkhtaivan,Kim, Doo Hwan
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- Superb-selective chemodosimetric signaling of sulfide in the absence and in the presence of CT-DNA and imaging in living cells by a plant alkaloid berberine analogue
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The present manuscript reports a lucrative design of a colorimetric and ratiometric chemodosimeter, 9-O-(2,4-dinitrobenzenesulfonyl)berberrubine (BER-S), with excellent water solubility for the superb selective detection of sulfides through a color alteration from yellow to red with a good limit of detection (LOD) of 56 nM in CP buffer solution (10 mM, pH 7.2). Interestingly, this work also includes a smart "turn-on" emission probe (BER-S/DNA complex) showing good linearity with an excellent LOD of 46 nM for recognizing sulfide anions. The probes, BER-S, and BER-S/DNA complex, displayed no interfering effect by other analytes or sulfur-containing inorganic compounds, like thiols. Characterization was carried out using IR, HRMS, and DFT for the BER-S probe, and time-resolved fluorescence lifetime measurement and fluorescence titration for the BER-S/DNA complex probe for elucidating their sensing mechanism. The detection of S2- in waste, tap, and drinking water by BER-S indicated its potential application in real sample analysis, while concentration variant cell imaging experiments (naked-eye red fluorescence) verified its cell-membrane permeability and capability for S2- imaging in living cells. This reaction-based sensing strategy in the presence of DNA may provide a potential platform for the design of a fluorescent chemodosimeter for extensive anion targets.
- Jana, Gopal Chandra,Khatun, Munira,Nayim, Sk,Das, Somnath,Maji, Anukul,Beg, Maidul,Patra, Anirudha,Bhattacharjee, Paromita,Bhadra, Kakali,Hossain, Maidul
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- Natural Berberine-Hybridized Benzimidazoles as Novel Unique Bactericides against Staphylococcus aureus
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Natural berberine-hybridized benzimidazoles as potential antibacterial agents were constructed to treat Staphylococcus aureus infection in the livestock industry. Bioassay showed that some new berberine-benzimidazole hybrids exhibited potent antibacterial efficacies, especially, the 2,4-dichlorobenzyl derivative 7d not only showed strong activity against S. aureus ATCC 29213 with the MIC value of 0.006 mM but also effectively eradicated bacterial biofilm and exhibited low toxicity toward mammalian cells. The drug combination experiments showed that compound 7d together with norfloxacin could enhance the antibacterial efficacy. Moreover, the 2,4-dichlorobenzyl derivative 7d did not show obvious propensity to develop bacterial resistance. Preliminary mechanism studies revealed that the active molecule 7d could damage the membrane integrity, stimulate ROS generation, and bind with DNA as well as S. aureus sortase A, thus exerting powerful antibacterial ability. In light of these facts, berberine-benzimidazole hybrid 7d showed a large potentiality as a new bactericide for treating S. aureus in the livestock industry.
- Sun, Hang,Ansari, Mohammad Fawad,Fang, Bo,Zhou, Cheng-He
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- Synthesis, DNA-binding affinities, and binding mode of berberine dimers
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Six novel berberine dimers (3a-f) were synthesized in 37-84% yield from the reaction of berberrubine (2) with dihaloalkanes of varying lengths from two to seven carbons. Their interactions with calf thymus (CT) DNA and three double helical oligodeoxynucleotides, d(AAGAATTCTT)2, d(AAGCATGCTT) 2, and d(TAAGAATTCTTA)2, were investigated by means of fluorometric titration and ethidium bromide (EB) displacement experiments. Compared with the monomeric parent berberine (1), these dimers' DNA-binding affinities increased up to approximately 100-fold, suggesting a cooperative interaction of the two berberine subunits in the molecules. Furthermore, these dimers linked by different spacers show a prominent structure-activity relationship when bound with oligodeoxynucleotides. The relative binding affinities are in the order of 3b > 3a > 3c > 3d > 3e > 3f with d(AAGAATTCTT)2 and d(TAAGAATTCTTA)2, and 3b > 3c > 3a > 3d > 3e > 3f with d(AAGCATGCTT)2. Dimer 3b, linked with a propyl chain, exhibits the highest binding affinity. This suggests that a propyl chain may be the most suitable spacer to bridge the two berberine units for DNA binding. Spectrophotometric titration and competitive EB displacement of berberine (1) and dimer 3b indicate that both berberine and its dimers form intercalating complexes with duplex DNA. A larger redshift, a stronger hypochromic effect, and a much higher EB displacement ratio, observed in 3b, indicate that the dimer is in more intimate contact with DNA than berberine. In addition, no obvious binding of canadine (4), a hydrogenated product of berberine, with CT DNA was observed, suggesting critical roles of the quaternary ammonium cation and planar structure in the DNA-binding of berberine.
- Qin, Yong,Pang, Ji-Yan,Chen, Wen-Hua,Cai, Zongwei,Jiang, Zhi-Hong
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- Discovery of novel berberine imidazoles as safe antimicrobial agents by down regulating ROS generation
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A series of novel berberine-based imidazole derivatives as new type of antimicrobial agents were developed and characterized. Most of them gave good antibacterial activity toward the Gram-positive and negative bacteria. Noticeably, imidazolyl berberine 3a exhibited low MIC value of 1 μg/mL against Eberthella typhosa, which was even superior to reference drugs berberine, chloromycin and norfloxacin. The cell toxicity and ROS generation assay indicated that compound 3a showed low cell toxicity. The interactive investigation by UV-vis spectroscopic method revealed that compound 3a could effectively intercalate into calf thymus DNA to form 3a-DNA complex which might further block DNA replication to exert the powerful antimicrobial activities. The binding behavior of compound 3a to DNA topoisomerase IB revealed that hydrogen bonds and electrostatic interactions played important roles in the association of compound 3a with DNA topoisomerase IB.
- Wen, Si-Qi,Jeyakkumar, Ponmani,Avula, Srinivasa Rao,Zhang, Ling,Zhou, Cheng-He
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- synthesis and evolution of berberine derivatives as a new class of antiviral agents against enterovirus 71 through the MEK/ERK pathway and autophagy
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Taking berberine (BBR) as the lead, 23 new BBR derivatives were synthesized and examined for their antiviral activities against four different genotype enterovirus 71 (EV71) strains with a cytopathic effect (CPE) assay. Structure-activity relationship (SAR) studies indicated that introduction of a suitable substituent at the 9-position might be beneficial for potency. Among them, compound 2d exhibited most potent activities with IC50 values of 7.12-14.8 μM, similar to that of BBR. The effect of 2d was further confirmed in a dose-dependent manner both in RNA and protein level. The mechanism revealed that 2d could inhibit the activation of MEK/ERK signaling pathway. Meanwhile, it could suppress the EV71-induced autophagy by activating AKT and inhibiting the phosphorylation of JNK and PI3KIII proteins. We consider BBR derivatives to be a new family of anti-EV71 agents through targeting host components, with an advantage of broad-spectrum anti-EV71 potency.
- Wang, Yan-Xiang,Yang, Lu,Wang, Hui-Qiang,Zhao, Xiao-Qiang,Liu, Ting,Li, Ying-Hong,Zeng, Qing-Xuan,Li, Yu-Huan,Song, Dan-Qing
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- Design, synthesis and biological evaluation of berberine-benzimidazole hybrids as new type of potentially DNA-targeting antimicrobial agents
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A series of novel berberine-benzimidazole derivatives were conveniently and efficiently synthesized and characterized by NMR, IR, MS and HRMS spectra. Most of the prepared compounds showed effective antimicrobial activities in contrast with clinical norfloxacin, chloromycin and fluconazole. Especially, compound 5d exhibited good anti-MRSA, anti-Escherichia coli, and anti-Salmonella typhi activity with low MIC values of 2–8?μg/mL, which were comparable or even superior to reference drugs. The preliminarily interactive investigation revealed that the most active compound 5d could effectively intercalate into DNA to form 5d-DNA complex and cleavage DNA by agarose gel electrophoresis experiments. It was also found that compound 5d was able to efficiently permeabilize the membranes of both Gram-positive (MRSA) and Gram-negative (E. coli DH52) bacteria. Experiments and molecular docking both showed that human serum albumin (HSA) could effectively transport compound 5d and hydrophobic interactions and hydrogen bonds play important roles in the association of compound 5d with HSA.
- Jeyakkumar, Ponmani,Zhang, Ling,Avula, Srinivasa Rao,Zhou, Cheng-He
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- Synthesis of linked berberine dimers and their remarkably enhanced DNA-binding affinities
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This communication describes the facile synthesis of five novel berberine dimers and their strong affinities toward double-stranded DNA. These berberine dimers were synthesized in 37-84% yields from the reaction of berberrubine with dihaloalkanes of varying lengths, and fully characterized by HRMS and 1H NMR. Compared with the monomeric parent berberine, these dimers showed greatly enhanced binding affinities up to approximately 100-fold, with two double helical oligodeoxynucleotides, d(AAGAATTCTT)2 and d(TAAGAATTCTTA)2, which was investigated by means of fluorescence spectrometry.
- Chen, Wen-Hua,Pang, Ji-Yan,Qin, Yong,Peng, Qian,Cai, Zongwei,Jiang, Zhi-Hong
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- Design, synthesis and evaluation of a baicalin and berberine hybrid compound as therapeutic agent for ulcerative colitis
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Structural modification of active natural compounds which were originated from Traditional Chinese Medicine (TCM) have showed great advantages in the development of new drugs. In TCM, “Huangqin - Huanglian” is a classic “medicine couple” that has been used to treat intestinal diseases for thousands of years, while baicalin and berberine are the major active compounds of Huangqin and Huanglian respectively. Based on this “medicine couple”, we designed and synthesized a new baicalin and berberine hybrid compound (BBH). Its molecular structure was confirmed by spectroscopy. The antibacterial activity of BBH was detected in vitro. Results indicated that the new hybrid compound exhibited the best antibacterial activity for proteobacteria as compared with its original synthetic materials (baicalin and berberine). In vivo, the effect of BBH on ulcerative colitis was also investigated. BBH treatment significantly ameliorated the disease symptoms and prevented the colon damage of ulcerative colitis. Furthermore, BBH showed a significant anti-inflammatory effect through regulating activities of SOD, MPO and expressions of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in colon tissue. Data also suggested that BBH was more superior than baicalin and berberine in ameliorating colonic damage. This indicated that the new hybrid compound BBH showed enhanced efficacy in treating ulcerative colitis.
- Jia, Dan,Dou, Yonghui,Li, Ziwen,Zhou, Xinxin,Gao, Ying,Chen, Keji,Cong, Weihong,Ma, Min,Wu, Zhengzhi,Li, Weimin
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- 13-hydroxylation of tetrahydroberberine in cell suspension cultures of some Corydalis species
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Liquid chromatography/atmospheric pressure chemical ionization-mass spectrometry was applied to biotransformation experiments in cultured cells of Corydalis ophiocarpa as well as C. ochotensis var. raddeana. Hydroxylation at C-13 of tetrahydroberberine was shown to take place in cell cultures as well as in C. ophiocarpa plants. N-Methylation of tetrahydroberberine occurred to form the α-N-metho salt incorporating the B/C-cis-quinolizidine system. Introduction of the C-13 methyl with berberine as substrate was confirmed to provide 13-methylberberine. In addition, the reversible oxidation-reduction of the C ring of protoberberines was demonstrated. Copyright
- Iwasa,Kamigauchi
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- Anti-Inflammation Associated Protective Mechanism of Berberine and its Derivatives on Attenuating Pentylenetetrazole-Induced Seizures in Zebrafish
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Epileptic seizures are characterized by synchronized discharges of neurons, leading to the activation of inflammatory responses that in turn contributes to seizure progression. Berberine (BBR), a bioactive constituent extracted from berberis, has been known to relieve seizures in rodent models. In this study, we synthesized two derivatives of berberine (BBR-D1 and BBR-D2) to compare their seizure reducing effect with BBR in pentylenetetrazole (PTZ)-induced seizures in zebrafish. We found a structure-activity relationship between hydrophilic/hydrophobic composition of the derivatives and their anticonvulsant activity. We also investigated the underlying mechanism related to their anti-inflammatory effect during seizures. BBR and its derivatives increased the seizure onset latency and suppressed the seizure-like behavior after PTZ treatment. Zebrafish larvae pretreated with BBR and its derivatives showed recovery on c-fos expression and neuronal discharges during seizures. The inflammatory responses occurred during the progression of seizures, including the recruitment of macrophages and neutrophils as well as an up-regulation of tumor necrosis factor alpha (TNFα), interleukin 1 beta (il1β), and interleukin 6 (il6). This effect was significantly suppressed by the pretreatment of BBR and its derivatives. Our results suggest that BBR and its derivatives attenuate PTZ-induced seizures and modulate anti-inflammatory effect to potentially protect zebrafish from the occurrence of further seizures. From the tested compounds, BBR-D1 (the hydrophilic berberrubine) showed the strongest seizure reducing effect. [Figure not available: see fulltext.].
- Zhang, Baoyue,Wang, Lizhen,Ji, Xiuna,Zhang, Shanshan,Sik, Attila,Liu, Kechun,Jin, Meng
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- Synthesis and biological evaluation of berberine derivatives bearing 4-aryl-1-piperazine moieties
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Piperazine moieties with disubstituted N-aryl groups are linked to the isoquinoline alkaloid, berberine, through a pentyloxy side chain, replacing its 9-methoxyl group. The nine synthesised compounds are screened for antioxidant potency, in vitro anticancer activities against Hela and Caski cervical cancer cell lines and for cytotoxicity towards Malin Darby canine kidney cell lines. Several compounds demonstrate significant antioxidant potency and most of the compounds exhibit equipotent, or better, anticancer activity when compared to berberine.
- Mistry, Bhupendra,Keum, Young-Soo,Kim, Doo Hwan
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- Berberine derivatives, preparation method thereof and application of berberine derivatives as p300 HAT small molecule inhibitor
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The invention discloses berberine derivatives, a preparation method thereof and an application of the berberine derivatives as a p300 HAT small molecule inhibitor, and belongs to the technical field of medicinal chemistry. An effective component berberine hydrochloride in a natural product coptis chinensis is taken as a research object and is subjected to structural modification and transformationso as to obtain a series of berberine hydrochloride derivatives. The berberine derivatives have the characteristics of high activity, high selectivity and high safety for p300 HAT, and solves the problems of high cytotoxicity, weak affinity, low activity and poor selectivity of existing p300 HAT small molecule inhibitors.
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Paragraph 0048-0050; 0054-0055; 0066-0070
(2021/02/10)
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- Preparation method of berberrubine hydrochloride
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The invention discloses a preparation method of berberrubine hydrochloride, and the method comprises the following steps: by using berberine hydrochloride as a raw material, mixing and heating berberine hydrochloride and N-methylpyrrolidone, performing cooling after the reaction is finished, adding an inert solvent, performing stirring, and performing crystallizing to obtain berberrubine hydrochloride. By adopting a new synthesis route and crystallization process, the yield and purity of the product are greatly improved, the yield of the route reaches 85-90%, the purity of the product reaches95% or above, and the method is simple to operate, mild in condition and beneficial to large-scale industrial production.
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Paragraph 0021-0042
(2021/03/13)
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- Novel berberine derivative as well as synthesis method and application thereof
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The invention discloses a novel berberine derivative as well as a synthesis method and application thereof, belongs to the field of imaging agents, and aims to derive the structure of isoquinoline alkaloid berberine, optimize derived sites on the basis of an early stage and introduce an F-containing side chain to prepare a series of probes with a myocardial targeting property. A 18F marker of theseries of compounds is successfully prepared through a marking experiment of positron nuclide 18F; the 18F-labeled novel berberine derivative is higher in myocardial uptake, raw materials are easy toobtain, the synthesis cost of a molecular probe is reduced, and clinical transformation is facilitated.
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Paragraph 0044-0046
(2021/01/29)
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- Discovery of C-9 modified berberine derivatives as novel lipid-lowering agents
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Berberine (BBR), a kind of quaternary ammonium benzylisoquinoline alkaloids with multiple pharmacological activities, has been regarded as a promising lipid-lowering agent in the field of drug repurposing. Particularly, the chemical modification at the C-9 position of BBR can remarkably improve its lipid-lowering efficacy. In this study, thirteen novel BBR derivatives were rationally designed, synthesized, and evaluated by preliminary pharmacological tests. The results showed that most compounds exhibited more potent hypolipidemic activities when compared with BBR and simvastatin. Among these compounds, compound 2h-1 and 2h-2 exhibited better activity profiling in these four tests involving with inhibition of total cholesterol (TCHO), triglyceride (TG), and low-density lipoprotein cholesterol (LDLC) and the increase of high-density lipoprotein cholesterol (HDLC). Correspondingly, the BBR analogs with 9-O-cinnamic moiety probably exhibited potent lipid-lowering activity, and should be exploited as an important versatile template for the development of BBR-like lipid-lowering agents.
- Li, Dong-Dong,Yu, Pan,Xu, Hui,Wang, Zhen-Zhong,Xiao, Wei,Zhao, Lin-Guo
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- COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATING NASH, NAFLD, AND OBESITY
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The present technology relates to methods of treating NASH, NAFLD and/or obesity using compounds of Formulas I, II, III, IV, V, and/or VI. The methods include administering to a subject suffering from one or more of non-alcoholic steatohepatitis (NASH), non- alcoholic fatty liver disease (NAFLD) and/or obesity a therapeutically effective amount of such a compound
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Paragraph 00196
(2021/04/10)
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- Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives to reduce SREBPs expression for the treatment of hyperlipidemia
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Statins play an important role in the treatment of hyperlipidemia, but drug resistance and adverse effects greatly limits their application. To discover new lipid-lowering drugs, three different series of tetrahydroprotoberberine derivatives (THPBs) were designed and synthesized. These compounds were first tested for their effects on viability of HepG2 cells and 21 compounds with the percent of cell viability over 90% were further screened to evaluate their ability to reduce total cholesterol (TC) and triglyceride (TG) levels. Among these derivatives, two compounds displayed significant down-regulation both intracellular of TC and TG content, especially compound 49 exhibited the greatest efficacy. Mechanistically, compound 49 promoted proteasomal degradation of SREBPs. Importantly, compound 49 displayed superior bioavailability (F = 65.1%) and obvious efficacy in the treatment of high fat diet induced obesity in vivo. Therefore, compound 49 is a promising candidate to develop new treatment of hyperlipidemia.
- Ge, Haixia,Zhang, Weitao,Yuan, Kai,Xue, Hanyue,Cheng, Hao,Chen, Weijiao,Xie, Yishi,Zhang, Jian,Xu, Xiaojun,Yang, Peng
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- Isoquinoline alkaloid as well as derivative, preparation method, pharmaceutical composition and application thereof
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The invention discloses isoquinoline alkaloid as well as a derivative, a preparation method, a pharmaceutical composition and application thereof. The structure of the compound is shown as a formula I shown in the description. The isoquinoline alkaloid derivative relates to an isomer, a diastereoisomer, an enantiomer, a tautomer, a solvate, a salt of the solvate, a pharmaceutically acceptable salt or a mixture of the isomer, the diastereoisomer, the enantiomer, the tautomer, the solvate, the salt of the solvate and the pharmaceutically acceptable salt of the compound. The isoquinoline alkaloid and the derivative thereof can reduce blood fat and improve insulin resistance of a body, have obvious curative effects on a cellular level and in an animal body, and can be used for preparing a medicine for preventing and/or treating the non-alcoholic fatty liver disease, and the compound is simple and convenient in synthesis method and easy to operate.
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Paragraph 0102-0105
(2021/05/29)
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- Synthesis method of berberrubine ester substances
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The invention discloses a synthesis method of berberrubine ester substances. The method comprises the following steps: using 4-dimethylaminopyridine as a catalyst and dicyclohexylcarbodiimide as a deacidifying agent, directly reacting berrubine with carboxylic acid in a certain solvent to generate the berrubine ester substances with bioactivity, reacting for 1.5-2 hours at the temperature of between 40 and 60 DEG C, basically finishing the reaction, filtering to remove solid substances while the reaction is hot, freezing overnight to separate out a target object, filtering, washing, drying andthe like to obtain a yellow crude product, and finally, separating the crude product by using a methanol dichloromethane column with the volume ratio of 1: 10, and further purifying the product to obtain the product. The yield of the product is 85.2%-93.4%, and the purity of the product is greater than 96%. Compared with traditional synthesis of berberrubine ester, the method has the advantages that the reaction yield is high, and the product is good in color and luster and high in purity; the method has the advantages of mild reaction conditions, short reaction time, fewer byproducts, accessible raw materials, simple operation, easy post-treatment and the like.
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Paragraph 0009; 0026-0031
(2020/12/30)
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- Synthesis and in vitro photocytotoxicity of 9-/13-lipophilic substituted berberine derivatives as potential anticancer agents
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The objective of this study was to synthesize the 9-/13-position substituted berberine derivatives and evaluate their cytotoxic and photocytotoxic effects against three human cancer cell lines. Among all the synthesized compounds, 9-O-dodecyl- (5e), 13-dodecyl- (6e), and 13-O-dodecyl-berberine (7e) exhibited stronger growth inhibition against three human cancer cell lines, (HepG2, HT-29 and BFTC905), in comparison with structurally related berberine (1). These three compounds also showed the photocytotoxicity in human cancer cells in a concentration-dependent and light dose-dependent manner. Through flow cytometry analysis, we found out a lipophilic group at the 9-/13-position of berberine may have facilitated its penetration into test cells and hence enhanced its photocytotoxicity on the human liver cancer cell HepG2. Further, in cell cycle analysis, 5e, 6e, and 7e induced HepG2 cells to arrest at the S phase and caused apoptosis upon irradiation. In addition, photodynamic treatment of berberine derivatives 5e, 6e, and 7e again showed a significant photocytotoxic effects on HepG2 cells, induced remarkable cell apoptosis, greatly increased intracellular ROS level, and the loss of mitochondrial membrane potential. These results over and again confirmed that berberine derivatives 5e, 6e, and 7e greatly enhanced photocytotoxicity. Taken together, the test data led us to conclude that berberine derivatives with a dodecyl group at the 9-/13-position could be great candidates for the anti-liver cancer medicines developments.
- Lin, Hong-Jhih,Ho, Jinn-Hsuan,Tsai, Li-Chen,Yang, Fang-Yu,Yang, Ling-Ling,Kuo, Cheng-Deng,Chen, Lih-Geeng,Liu, Yi-Wen,Wu, Jin-Yi
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supporting information
(2020/02/18)
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- Dual-channel berberine-based fluorescent probe for detecting Hg/ClO as well as preparation method and application thereof
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The invention discloses a dual-channel berberine-based fluorescent probe for detecting Hg/ClO as well as a preparation method and application of the dual-channel berberine-based fluorescent probe. According to the invention, berberine is used as a raw material to prepare the dual-channel berberine fluorescent probe for detection of Hg/ClO. Berberine hydrochloride 1 is subjected to methoxy and chloride ion removal to obtain a ketone compound 2; the compound 2 is acidified and isomerized to obtain a phenolic compound 3; Duff formylation reaction is carried out on the compound 3 toobtain a p-hydroxy aldehyde compound 4; and the compound 4 and thiosemicarbazide are condensed to obtain a thiosemicarbazide Schiff base compound 5. The compound 5 can specifically recognize Hg and ClO, and the probe emits orange red fluorescence in the presence of Hg under the irradiation of 365nm ultraviolet light. In the presence of ClO, the probe emits green fluorescence, and inthe presence of other anions and metal ions, fluorescence does not occur. Therefore, the compound 5 can be used as a dual-channel fluorescent probe and has good application value.
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- The invention relates to a catechol is raw material of synthetic small bo hong alkali method (by machine translation)
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The invention relates to a catechol is raw material of synthetic small bo hong alkali method, relates to a method for drug synthesis, in order to catechol as raw materials, with the catechol 2 - methyl chloride selective methylation reaction get O-methoxyphenol, continue to selective hydroformylation reaction to obtain the 2 - hydroxy - 3 - methoxybenzaldehyde; with the catechol 2 - methyl chloride methylene compounds obtained by reaction of pepper link, to continue to work with 2 - chloroethylamine catalytic addition reaction pepper ethylamine; the pepper ethylamine with 2 - hydroxy - 3 - methoxybenzaldehyde in a nickel-based catalyst "one-pot" condensation under the conditions of the hydrogenation reaction, the reaction product is hydrochloric acid, cooling of the crystal, and filtering to obtain the hydrochloride condensate; will be hydrochloride compression compound refined, continue to work with the glyoxal, under the condition of a copper-based catalyst, a cyclization reaction is carried out, the reaction product after passing through the refining process, hydrochloric acid, cooling crystallization, filtration washing to obtain the product of the ABS red alkali. The industrialization of this invention fully synthetic production of the ABS red alkali, to create a small bo hong alkali drug chemical synthesis method. (by machine translation)
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- The invention relates to a raw material for the preparation of the ABS guaiacol red alkali method (by machine translation)
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The invention relates to a raw material for the preparation of the ABS guaiacol red alkali method, relates to a pharmaceutical preparation method, the present invention in order to guaiacol as raw materials, through the selective hydroformylation reaction to obtain the 2 - hydroxy - 3 - methoxybenzaldehyde; to catechol as raw materials, the reaction methylene compounds pepper link, catalytic addition a footwork of to the pepper ethylamine; 2 - hydroxy - 3 - methoxy benzaldehyde with pepper ethylamine in a nickel-based catalyst "one-pot" condensation under the conditions of the hydrogenation reaction, the reaction product is hydrochloric acid, cooling of the crystal, the hydrochloride compression compound crystal refined, continue to work with the glyoxal, under the condition of a copper-based catalyst, a cyclization reaction is carried out, the reaction product after passing through the refining process, hydrochloric acid, cooling crystallization, filtration washing to obtain the product of the ABS red alkali. The invention catechol as raw materials, the reaction process for preparing methylene compounds after the pepper link, one-step catalytic addition reaction pepper ethylamine, shorten the technological process, overcomes the use of toxic cyanide, process green; process solvent recycling. (by machine translation)
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- Method for preparing berberrubine from o-vanillin as raw material
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The invention provides a method for preparing berberrubine from o-vanillin as a raw material and relates to a preparation method of a pharmaceutical raw material. The method comprises following steps:o-vanillin is taken as the raw material, o-vanillin and homopiperonylamine are added to a reaction kettle respectively, a nickel-based catalyst and a solvent are added, hydrochloric acid is added toa reaction product, cooling crystallization is performed, a crystal substance and glyoxal are put into an acetic acid and acetic anhydride solvent, a copper-based catalyst is added, and a mixture is subjected to a cyclization reaction; hydrochloric acid and an oxidizing agent are added to a reaction product, ammonium hydroxide is added to a reaction liquid, activated carbon is added, and a reaction solution is obtained; hydrochloric acid is added to the reaction solution, cooling crystallization and filtering are performed, and a primary crystal product is obtained; the primary crystal productis washed with ethanol and dried, and the product berberrubine is obtained. The raw materials are available, time and energy are saved, and cost is reduced; by means of industrial production of berberrubine, clinical requirements of berberrubine in current resistance to tumor, hypertension, arrhythmia and hyperglycemia and treatment of Alzheimer disease are met, and an effective drug is providedfor relieving pain of patients.
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- Novel carbohydrate modified berberine derivatives: Synthesis and: In vitro anti-diabetic investigation
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Berberine is a bioactive alkaloid used in Chinese medicine and has numerous positive effects on biological systems. This paper describes the facile and highly efficient synthesis of some carbohydrate modified berberine derivatives, and conjugation of the carbohydrate moiety with berberine was finished by "click" chemistry. The cytotoxicity and anti-diabetic measurements of all berberine derivatives were accomplished on HepG2 cell lines, and the results indicated that most of the derivatives exhibit higher anti-diabetic activity than berberine. The mannose modified berberine derivative has significantly lower cytotoxicity than berberine, and the induced IC50 value of this derivative is nearly 1.5 times that of berberine. Furthermore, this mannose modified berberine derivative exhibits high anti-diabetic activity at both high and low drug concentrations, thereby indicating its potential application for the development of novel anti-diabetic drugs.
- Han, Liwen,Sheng, Wenlong,Li, Xiaobin,Sik, Attila,Lin, Houwen,Liu, Kechun,Wang, Lizhen
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p. 598 - 605
(2019/04/30)
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- Synthetic method of 9-O-substituted phenoxyl alkyl berberine derivative
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The invention discloses a synthetic method of a 9-O-substituted phenoxyl alkyl berberine derivative. The method comprises the following steps: by taking tetrabutylammonium bromide as a phase transfercatalyst and DMF (Dimethyl Formamide) as a solvent, first, carrying out a reaction on alpha, omega-dibromo alkane and phenol to synthesize bromoalkyl phenyl ether; then carrying out a reaction directly with berberrubine at 80 DEG C for 4 hours; after reaction, pouring the mixture into ice water while being hot, cooling the mixture to separate out a solid; and then carrying out filtration and recrystallization of dichloromethane and absolute methanol (V/V=10: 1) to obtain a yellow powder solid which is 9-O-substituted phenoxyl alkyl berberine derivative. Compared with a conventional method of synthesizing the 9-O-substituted phenoxyl alkyl berberine derivative, the method has the advantages of being mild in reaction condition, high in efficiency, few in byproduct, short in time, simple to operate, good in color and luster of products, high in purity and the like, and has a relatively high actual application prospect.
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Paragraph 0012; 0013
(2019/01/08)
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- Berberine derivative and use thereof
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The invention discloses a berberine derivative for treating bacterium infection, and a use for thereof. The berberine derivative has a structure shown in the description. Experiments prove that the berberine derivative has positive ion charges under physiological conditions, and has the characteristics of broad antibacterial spectrum, good biocompatibility, good water solubility, strong targetingand low toxicity, a preparation method has the advantages of simplicity, easiness in implementing, high yield, and significant curative effect in the antibacterial field.
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Paragraph 0023; 0058-0059
(2018/06/15)
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- Synthesis and biological evaluation of new berberine derivatives as cancer immunotherapy agents through targeting IDO1
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To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty–five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure–activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71–90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation.
- Wang, Yan-Xiang,Pang, Wei-Qiang,Zeng, Qing-Xuan,Deng, Zhe-Song,Fan, Tian-Yun,Jiang, Jian-Dong,Deng, Hong-Bin,Song, Dan-Qing
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p. 1858 - 1868
(2017/11/17)
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- A berberine 9 - bit pyrazole derivative and its preparation and use (by machine translation)
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The present invention of berberine (berberine) structure modification has synthesized the model of berberine derivatives, its structure is represented by general formula (I) of a compound. The invention relates to the preparation of berberine derivatives, antioxidant activity and anti-cancer effects. The experiment proves, berberine derivatives of the present invention has better oxidation resistance, generating active oxygen ROS to induce cancer cell death of the cancer cell, to a plurality of cancer cell strain has significant inhibition function, can be used for preparing anti-tumor drug. (by machine translation)
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Paragraph 0055; 0056
(2018/08/04)
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- Tetrahydroberberine thiadione compounds as well as preparation method and application thereof
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The invention relates to tetrahydroberberine thiadione compounds as well as a preparation method and an application thereof and belongs to the technical field of chemical synthesis. The tetrahydroberberine thiadione compounds are shown in a general formula I-X, have certain inhibition activity for growth of gram-positive bacteria, gram-negative bacteria and fungi, can be used for preparing drugs for resisting bacteria and/or fungi, have no obvious drug resistance, can be combined with norfloxacin and fluconazole to more efficiently inhibit growth of bacteria and fungi and can also be intercalated into DNA to be used as a DNA intercalating agent. Besides, the preparation materials are simple, cheap and easy to obtain, the synthesis route is short and the compounds have great significance inapplication in infection resistance.
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Paragraph 0061; 0064
(2018/11/03)
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- Preliminary studies of berberine and its semi-synthetic derivatives as a promising class of multi-target anti-parkinson agents
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Parkinson’s disease (PD) is a neurodegenerative disorder bearing motor and nonmotor symptoms. The treatment today is symptomatical rather than preventive or curative and this leaves the field open for the search of both novel molecular targets and drug candidates. Interference with α-synuclein fibrillation, monoamine oxidase (MAO) inhibition, modulation of adenosine receptors and the inhibition of specific phosphodiesterase (PDE) isoforms are some of the currently pursued strategies. We synthesised and studied some semi-synthetic berberine derivatives using a set of in silico tools. We evaluated their drug-likeness and tested the compounds against a set of target proteins involved in the onset or progression of PD, with a particular attention to MAO-B. Preliminary in vitro assay on MAO-B confirmed our in silico predictions.
- Ribaudo, Giovanni,Zanforlin, Enrico,Canton, Marcella,Bova, Sergio,Zagotto, Giuseppe
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supporting information
p. 1 - 7
(2017/10/06)
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- Synthesis and identification of novel berberine derivatives as potent inhibitors against TNF-α-induced nf-κb activation
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Twenty-three new berberine (BBR) analogues defined on substituents of ring D were synthesized and evaluated for their activity for suppression of tumor necrosis factor (TNF)-α-induced nuclear factor (NF)-κB activation. Structure–activity relationship (SAR) analysis indicated that suitable tertiary/quaternary carbon substitutions at the 9-position or rigid fragment at position 10 might be beneficial for enhancing their anti-inflammatory potency. Among them, compounds 2d, 2e, 2i and 2j exhibited satisfactory inhibitory potency against NF-κB activation, with an inhibitory rate of around 90% (5 μM), much better than BBR. A preliminary mechanism study revealed that all of them could inhibit TNF-α-induced NF-κB activation via impairing IκB kinase (IKK) phosphorylation as well as cytokines interleukin (IL)-6 and IL-8 induced by TNF-α. Therefore, the results provided powerful information on further structural modifications and development of BBR derivatives into a new class of anti-inflammatory candidates for the treatment of inflammatory diseases.
- Wang, Yan-Xiang,Liu, Lu,Zeng, Qing-Xuan,Fan, Tian-Yun,Jiang, Jian-Dong,Deng, Hong-Bin,Song, Dan-Qing
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- Novel benzimidazolyl tetrahydroprotoberberines: Design, synthesis, antimicrobial evaluation and multi-targeting exploration
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A series of novel benzimidazolyl tetrahydroprotoberberines were conveniently designed and efficiently synthesized from berberine via direct cyclization of tetrahydroprotoberberine aldehyde and o-phenylene diamines under metal-free aerobic oxidation. All the new compounds were characterized by IR, 1H NMR, 13C NMR and HRMS spectra. The antimicrobial evaluation revealed that the 5-fluorobenzimidazolyl derivative 5b was the most active antibacterial and antifungal molecule with broad spectrum in comparison to Berberine, Chloromycin, Norfloxacin and Fluconazole. It triggered almost no resistance development against MRSA even after 15 passages. Further studies demonstrated that compound 5b could not only effectively interact with Topo IA by hydrogen bonds, but also intercalate into calf thymus DNA and cleave pBR322 DNA, which might be responsible for its powerful bioactivities.
- Jeyakkumar, Ponmani,Liu, Han-Bo,Gopala, Lavanya,Cheng, Yu,Peng, Xin-Mei,Geng, Rong-Xia,Zhou, Cheng-He
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p. 1737 - 1743
(2017/04/04)
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- Synthesis and anti-inflammatory effects of a series of novel 9-O-substituted berberine derivatives
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Berberine owns multiple pharmacological activities, especially anti-inflammatory activity. To enhance the anti-inflammatory therapeutic efficiency of berberine, a series of novel 9-O-substituted berberine derivatives (5a–5d) were synthesized and their anti-inflammatory activities were evaluated. 13C-NMR, 1H-NMR, IR and high resolution mass spectrum (HRMS) results indicated that these derivatives were successfully synthesized. The xylene-induced inflammatory mice model demonstrated that these derivatives showed dose-dependent inhibition of ear inflammatory swelling. Comparing to berberine, ibuprofen and naproxen-modified berberine derivatives enhanced anti-inflammatory activities, while aspirin and nicotinic acid-modified berberine derivatives showed lower anti-inflammatory effects at the same dosages. This could be attributed to the enhanced inhibition of secretion of cytokines, including interleukin-6 and tumor necrosis factor-α, by ibuprofen and naproxen berberine derivatives, while aspirin and nicotinic acid berberine derivatives showed lower inhibition of tumor necrosis factor-α than berberine. These results suggest that ibuprofen and naproxen-modified berberine derivatives are promising new anti-inflammatory drug candidates.
- Liu, Zhenbao,Wang, Xiaohong,Zhang, Hang,Zhang, Shanshan,Li, Yiqian,Liu, Yanfei,Peng, Dongming
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p. 672 - 679
(2017/02/15)
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- Double-berberine derivative and purpose
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The invention discloses a double-berberine derivative and a purpose. The double-berberine derivative has the following structure shown as the accompanying drawing. The double-berberine derivative provided by the invention has cationic charge under the physiological conditions, and has the characteristics of wide antibacterial spectrum, good biocompatibility, good water solubility, high targeting performance and low toxicity; the preparation method is simple; the implementation is easy; the yield is high; the obvious treatment effect is achieved in the antisepsis aspect.
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Paragraph 0020; 0033; 0034
(2017/01/17)
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- Preparation method and application of diberberine derivative
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The invention discloses a d diberberine derivative, a preparation method and application. The diberberine derivative has a structure shown as follows. The diberberine derivative has the advantages of high biocompatibility, high water solubility, high targeting performance and low toxicity, the preparation method is simple and easy to implement and high in yield and has remarkable treatment effect in the anti-inflammatory aspect.
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Paragraph 0025; 0064; 0065
(2017/05/19)
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- Synthesis and hypoglycemic activity of 9-O-(lipophilic group substituted) berberine derivatives
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A series of 9-O-(lipophilic group substituted) berberine derivatives were synthesized and evaluated for their cytotoxicity and hypoglycemic activity against HepG2 cells. All the results indicated that most of the synthesized compounds exhibited lower cytotoxicity and a certain degree of hypoglycemic activity. Especially the compounds 5g and 5h displayed dramatically increased hypoglycemic activity compared with berberine, and the cytotoxicity maintained or even lower than berberine, indicating that they are potential candidates for new anti-type 2 diabetes mellitus drugs.
- Zhang, Shanshan,Wang, Xiaohong,Yin, Weicheng,Liu, Zhenbao,Zhou, Mi,Xiao, Daipeng,Liu, Yanfei,Peng, Dongming
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supporting information
p. 4799 - 4803
(2016/09/13)
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- Berberine synthesis of derivatives thereof in the preparation of doxorubicin-tumor drugs and in coordination with the application of the anti-tumor pharmaceutical compositions
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The invention relates to berberine derivatives as well as a preparation method and an application of the berberine derivatives. The general formula of the berberine derivatives is shown in the specification, where R is alkyl, benzyl, substituted benzyl, phenyl, substituted phenyl, a heterocyclic group or a substituted heterocyclic group. The invention also relates to a composition of the berberine derivatives and adriamycin and an application of the compositions in preparation of an anti-tumor drug. The berberine derivatives disclosed by the invention have not only anti-tumor effects alone and in combination with adriamycin and but also have a certain protective effect on myocardial damage, weight loss and intestinal epithelial cells induced by the treatment, thereby being an ideal synergistic combination drug during the treatment of cancer by virtue of adriamycin.
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Paragraph 0048; 0049
(2016/11/21)
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